Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, 08028, Spain.
Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA.
Nat Commun. 2022 Nov 26;13(1):7279. doi: 10.1038/s41467-022-34925-y.
Forkhead box H1 (FoxH1) is an essential maternal pioneer factor during embryonic development that binds to specific GG/GT-containing DNA target sequences. Here we have determined high-resolution structures of three FoxH1 proteins (from human, frog and fish species) and four DNAs to clarify the way in which FoxH1 binds to these sites. We found that the protein-DNA interactions extend to both the minor and major DNA grooves and are thus almost twice as extensive as those of other FOX family members. Moreover, we identified two specific amino acid changes in FoxH1 that allowed the recognition of GG/GT motifs. Consistent with the pioneer factor activity of FoxH1, we found that its affinity for nucleosomal DNA is even higher than for linear DNA fragments. The structures reported herein illustrate how FoxH1 binding to distinct DNA sites provides specificity and avoids cross-regulation by other FOX proteins that also operate during the maternal-zygotic transition and select canonical forkhead sites.
叉头框蛋白 H1（FoxH1）是胚胎发育过程中必不可少的母体先驱因子，它能与特定的 GG/GT 富含 DNA 靶序列结合。在此，我们确定了三种 FoxH1 蛋白（来自人类、青蛙和鱼类物种）和四种 DNA 的高分辨率结构，以阐明 FoxH1 与这些位点结合的方式。我们发现，蛋白-DNA 相互作用延伸到小沟和大沟，因此几乎是其他 FOX 家族成员的两倍。此外，我们在 FoxH1 中鉴定出两个特定的氨基酸变化，使它能够识别 GG/GT 基序。与 FoxH1 的先驱因子活性一致，我们发现它与核小体 DNA 的亲和力甚至高于线性 DNA 片段。本文报道的结构阐明了 FoxH1 如何与不同的 DNA 位点结合以提供特异性，并避免其他也在母-合子过渡期间起作用并选择典型叉头位点的 FOX 蛋白的交叉调控。
